The research focus of this proposal is the development of a novel bioanalytical imaging device, the scanning mass spectrometer (SMS) probe, a powerful nanoscale tool for cell biology, enabling biochemical imaging of live cells and tissues. The SMS probe is based on a novel approach to electrospray ionization, which allows for the marriage of the mass spectrometer ion source with an atomic force microscope (AFM). The AFM-SMS-probe will have sub-cellular resolution, and provide for transient biological imaging mass spectrometry, capabilities that are not possible with current technologies. The result is a nanoscale device capable of detecting bio-molecules within or excreted from living cells under physiological conditions. The candidate's long-term goal is application of the AFM-SMS probe to investigations of significant and otherwise inaccessible problems of cell biology. The career development plan and research plan describe the methodology by which the candidate will accomplish three goals: (1) augmentation of his training in engineering and physics by developing expertise in biomedical fields, to prepare him to achieve his long-term objectives; (2) development, optimization, and characterization of the AFM-SMS probe; and (3) demonstration and validation of the technology, with progressively challenging applications. [unreadable] [unreadable] The device will be made using micro/nano fabrication techniques, stepping through increasing levels of complexity, with testing and improved design at each stage. Experiments for characterization and probe optimization will transition, as the technology matures and is better understood, from simple artificial systems, to synthetic lipid bilayers mimicking cell membranes, and finally to cell cultures. Theoretical models of the device operation will be used to guide and enhance probe design and operation optimization efforts. [unreadable] [unreadable] Relevance: The proposed research will result in the development of a new imaging tool for tissue/cell investigations which will dramatically expand the capabilities of researchers in multiple health-related fields. Specifically, it will increase the ability to identify spatial distributions, and their changes with time, of metabolites, peptides, and proteins, within and around living cells. It will therefore add a new dimension to proteomics and metabolomics, areas having major impacts in the fields of biology, medicine, and pharmacology through identification of new clinical markers of diseases, new drugs, and new drug targets. [unreadable] [unreadable] [unreadable]